Process for production of phenoxy-substituted 2-pyridone compounds

ABSTRACT

3-Phenoxy-2-pyridone compound can be produced by making the amide compound of the formula (1): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R is optionally substituted phenyl;
 
react with a malonoaldehyde derivative such as 3-alkoxypropenal and the like in the presence of a protonic acid.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Section 371 of International Application No.PCT/JP03/007843, filed Jun. 20, 2003, which was published in theJapanese language on Dec. 31, 2003, under International Publication No.WO 2004/000812 A1 the disclosure of which is incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a process for producingphenoxy-substituted 2-pyridone compounds, which is useful forintermediates of medicinal and agricultural product, especiallyherbicidal compound.

BACKGROUND ART

It is known that 2-pyridone compounds can be produced by making3-oxobutanamide react with a various kind of ketone compound.Specifically, 4,6-dimethyl-2-pyridone is obtained by making3-oxobutanamide react with acetone in the presence of polyphosphoricacid; 3-acetyl-4,6-dimethyl-2-pyridone is obtained by making3-oxobutanamide react with pentan-2,4-dione in the presence of hydrogenchloride or polyphosphoric acid; and5-ethoxycarbonyl-4,6-dimethyl-2-pyridone is obtained by making3-oxobutanamide react with ethyl acetoacetate in the presence ofpolyphosphoric acid (Chem. Pharm. Bull. 28(7) 2244–2247 (1980). J. Chem.Soc. (C), 1967, 1836–1839).

DISCLOSURE OF INVENTION

The present inventors have intensively studied a process for producing a2-pyridone compound substituted at 3-position with optionallysubstituted phenoxy, that is useful for intermediates of medicinal andagricultural product, especially herbicidal compound. As a result, thepresent inventors was found out that 3-phenoxy-2-pyridone compound onlysubstituted at 3-position can be obtained by 2-phenoxy-3-oxobutanamidecompound, in which the phenoxy can be substituted, react with a certainof malonaldehyde derivative or malonaldehyde, thereby completing thepresent invention.

The present invention provides a process (hereinafter, referred to asthe present process) for producing a pyridone compound of the formula(2) (hereinafter, referred to as the present pyridone compound):

-   -   wherein R is defined below;        which comprises making an amide compound of the formula (1)        (hereinafter, referred to as the present amide compound):

-   -   wherein R represents an optionally substituted phenyl;        react with at least one compound (hereinafter, referred to as        the present malonaldehyde derivative) selected from the group        consisting of 3-alkoxypropenal of the formula (3),        3,3-dialkoxypropanal of the formula (4),        1,3,3-trialkoxy-1-propene of the formula (5),        1,1,3,3-tetraalkoxypropane of the formula (6), and        malonaldehyde:

-   -   wherein R⁹ represents alkyl (e.g. C1–C3 alkyl such as methoxy,        ethoxy and the like);        in the presence of a protonic acid.

Furthermore, the present invention also provides a process for producinga pyridone compound of the formula (B):

-   -   wherein R¹ and R² are defined below;        by using an amide compound of the formula (A):

-   -   wherein R¹ represents a halogen atom or nitro, and R² represents        a hydrogen atom or halogen atom;        as the present amide compound.

The substituent on the optionally substituted phenoxy of the presentamide compound, which is a starting compound of the present process, andthe present pyridone compound includes, for example, a halogen atom(e.g. a fluorine atom, chlorine atom, bromine atom and the like); alkyl(e.g. C1–C4 alkyl such as methyl, ethyl, propyl, isopropyl and thelike); alkoxy (e.g. C1–C4 alkoxy such as methoxy, ethoxy, propoxy,isopropoxy and the like); haloalkyl (e.g. trifluoromethyl,pentafluoroethyl); nitro; cyano; and 5–6 membered heterocyclic radical(e.g. 1,2,3,6-tetrahydro-2,6-dioxopyrimidin-1-yl,1,6-dihydro-6-oxopyridazin-1-yl and he like). The optionally substitutedphenoxy includes, for example, phenoxy and he phenoxy shown with thescheme:

-   -   wherein R¹ and R² is defined above.

The present amide compound includes, for example, the compound shownwith the scheme:

The present malonaldehyde derivative means malonaldehyde, or formalcondensation products of malonaldehyde and alcohol, which isspecifically at least one malonaldehyde derivative selected from thegroup consisting of 3-alkoxypropenal of the formula (3),3,3-dialkoxypropanal of the formula (4), 1,3,3-trialkoxy-1-propene ofthe formula (5), 1,1,3,3-tetraalkoxypropane of the formula (6).3-Alkoxypropenal of the formula (3) includes, for example,3-methoxypropenal and 3-ethoxypropenal. 3,3-Dialkoxypropanal of theformula (4) includes, for example, 3,3-dimethoxypropanal and3,3-diethoxypropanal. 1,3,3-Trialkoxy-1-propene of the formula (5)includes, for example, 1,3,3-trimethoxy-1-propene and1,3,3-triethoxy-1-propene. 1,1,3,3-Tetraalkoxypropane of the formula (6)includes, for example, 1,1,3,3-tetramethoxypropane and1,1,3,3-tetraethoxypropane.

In the present process, 1,1,3,3-tetraalkoxypropane of the formula (6) ispreferable compound as the malonaldehyde derivative, considering thefactor of obtainability and the like.

The protonic acid to be used in the present process means a substancehaving a strong tendency to donate a proton, namely in the definition ofBrønsted acids and bases theory based on donating and accepting ofproton. Specifically, the protonic acid includes hydrogen halides (e.g.hydrogen chloride, hydrogen bromide and the like), phosphoric acid,polyphosphoric acid, sulfuric acid, trihaloacetic acid (e.g.trichloroacetic acid, trifluoroacetic acid and the like), sulfonic acid(e.g. chlorosulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,trifluoromethanesulfonic acid and the like) and the mixture thereof;preferably protonic acids having 2.5 or lower pKa, which is an aciddissociation constant in water.

The reaction of the present process may be carried out in a solvent. Thesolvent to be used includes, for example, aromatic hydrocarbons such astoluene, xylene and the like; halogenated aromatic hydrocarbons such aschlorobenzene, dichlorobenzene, benzotrifluoride and the like;halogenated aliphatic hydrocarbons such as chloroform,1,2-dichloroethane and the like; alcohols such as hexafluoroisopropanoland the like; and the mixture thereof.

In the reaction, 1 to 10 moles of the present malonaldehyde derivativeand catalytic to excess amount (e.g. 0.1 to 1000 moles, preferably 1 to10 moles) of the acid are usually used, relative to 1 mole of thepresent amide compound.

The reaction temperature of the reaction is usually in a range of 0 to150° C., preferably 20 to 100° C., and the reaction time is usually in arange of 0.5 to 72 hours, yet they are changeable by an amount andspecies of the protonic acid to be used.

The reaction is carried out with adding the present amide compound andthe present malonaldehyde derivative into the protonic acid or a mediumdiluted the proton acid with the above-mentioned solvent. In this case,it is allowed that all of the proton acid is used at once at startingreaction; and a part of the proton acid is used at starting reaction anda rest of the proton acid is added as according to progress of thereaction. The present amide compound and the present malonaldehyde maybe added all at once into the protonic acid or a medium diluted theproton acid with the above-mentioned solvent; but preferably, thepresent amide compound and the present malonaldehyde should be addedprogressively as according to the progress of the reaction.

The progress of the reaction can monitored, for example, by sampling apart of the reaction mixture and subjecting it to chromatography (e.g.thin layer chromatography, high performance liquid chromatography andthe like) to analyze a remaining amount of the amide compound of theformula (1) in the reaction mixture.

The present pyridone compound can be isolated from the reaction mixtureafter completion of the reaction by the following procedure:

-   1) Diluting the reaction mixture after completion of the reaction    with a hydrophobic organic solvent; washing it with saturated sodium    chloride aqueous solution, saturated sodium bicarbonate aqueous    solution or the like; drying the obtained organic layer; and    concentrating it to remove the solvent completely.-   2) Diluting the reaction mixture after completion of the reaction    with a hydrophobic organic solvent; washing it with saturated sodium    chloride aqueous solution, saturated sodium bicarbonate aqueous    solution or the like; partially concentrating it at 80 to 120° C.    and cooling; and filtering off and drying the generated solid.-   3) Partially concentrating the reaction mixture after completion of    the reaction; pouring it a mixture of water and a hydrophilic    organic solvent at any ratio; and filtering off and drying the    generated solid.-   4) Poring the reaction mixture after completion of the reaction into    water; adjusting pH of the water layer to about neutral; removing    the organic solvent with azeotropic distillation; and drying the    generated solid.

The hydrophobic organic solvent to be used in the post-treatmentprocedure includes, for example, esters such as ethyl acetate and thelike; halogenated aliphatic hydrocarbons such as chloroform and thelike; halogenated aromatic hydrocarbons such as chlorobenzene,dichlorobenzene, benzotrifluoride and the like; ketones such as methylisobutyl ketone and the like; and the mixture thereof. The hydrophilicorganic solvent includes, alcohols such as methanol, ethanol, isopropylalcohol, t-butyl alcohol and the like.

The isolated present pyridone compound can be purified bychromatography, recrystallization, washing with a poor solvent, and thelike.

The present amide compound to be used in the present process can beproduced, for example, by making the phenol compound of the formula (7)react with the amide compound of the formula (8) (e.g.2-chloro-3-oxobutanamide):

-   -   wherein X represents a halogen atom, and R is defined below.

The reaction is usually carried out in the presence of base in asolvent. The solvent to be used includes, for example, aromatichydrocarbons such as toluene, xylene and the like; acid amides such asN,N-dimethylformamide and the like. The base to be used includes, forexample, inorganic bases such as sodium carbonate, potassium carbonateand the like; tertiary amines such as triethylamine, tributylamine andthe like.

In the reaction, 1 to 1.5 mole of the amide compound of the formula (8)and 1 to 3 mole of the base are usually used, relative to 1 mole of thephenol compound of the formula (7).

The reaction temperature of the reaction is usually in a range of 20 to150° C., and the reaction time is usually in a range of 0.5 to 24 hours.

The present amide compound can be isolated from the reaction mixtureafter completion of the reaction, for example, by diluting the reactionmixture with organic solvent, washing it with saturated sodium chlorideaqueous solution, saturated sodium bicarbonate aqueous solution or thelike, drying and concentrating the obtained organic layer. The isolatedamide compound can be purified by chromatography, recrystallization andthe like.

The present malonaldehyde derivative to be used in the present processis known compound itself, or can be produced according to the methoddescribed in a public document.

As the public document, the following documents are exemplified.

-   Japanese Publication of unexamined application S52-97905, for    3-alkoxypropenal of the formula (3);-   J. Chem. Soc., Chem. Commun., (20) 1421–1422 (1991), for    3,3-dialkoxypropanal of the formula (4);-   Tetrahedron Lett., 29 (29) 3597–3598 (1988), for    1,3,3-trialkoxy-1-propene of the formula (5);-   J. Org. Chem. 53 (13) 2920–2925 (1988), for    1,1,3,3-tetraalkoxypropane of the formula (6);-   J. Org. Chem., 50 3585–3592 (1985), for malonaldehyde.

The present pyridone compound produced by the present process is usefulfor intermediates of medicinal and agricultural product. For example,the pyridine compound of the formula (D) can be produced by making thecompound of the formula (B) react with the diazo acetic acid estercompound of the formula (C) in the presence of rhodium (II) salt, borontrifluoride, p-toluenesulfonic acid or the like. The obtained pyridinecompound of the formula (D) is useful for an active ingredient ofherbicidal composition (European patent application publicationEP1122244 A1).

-   -   wherein R³ represents C1–C6 alkoxy.

In the case of the reaction in the presence of rhodium (II) salt; thereaction is usually carried out in a solvent, the reaction temperatureis in a range of 60 to 120° C., and the reaction time is in a range ofinstant to 72 hours. The solvent to be used includes, for example,halogenated hydrocarbons such as 1,2-dichloroethane and the like.Usually, the amount of diazoacetate compound of the formula (C) is 0.5to 2 moles, and the amount of the rhodium (II) salt is 0.01 to 0.05,relative to 1 mole of the compound of the formula (B). These amount canbe changeable according to the reaction condition. The rhodium (II) saltto be used includes, for example, rhodium (II) trifluoroacetate dimer.

After completion of the reaction, the pyridine compound of the formula(D) can be isolated from the reaction mixture by subjecting the reactionmixture to the post-treatment such as filtering the reaction mixture andconcentrating the filtrate; and diluting the reaction mixture with anorganic solvent and separated from sodium bicarbonate aqueous solution,drying and concentrating the obtained organic layer; and the like. Theisolated pyridine compound can be purified by chromatography and thelike.

The present invention will be further illustrating by the followingproduction examples and the like; however the present invention is notlimited to these examples. Additionally, “part” means a part by weightin the following description.

PRODUCTION EXAMPLE 1

Under nitrogen atmosphere, 57 mg of 3-oxo-2-phenoxybutanamide and 49 mgof 1,1,3,3-tetramethoxypropane were added into 2 ml of 25% hydrogenbromide solution in acetic acid, and stirred at 50° C. for 2.5 hours andat 100° C. for 2 hours. In the reaction mixture were added 80 ml ofethyl acetate and 30 ml of saturated sodium chloride aqueous solution,and the mixture was separated.

The organic layer was washed once with 30 ml of saturated sodiumchloride aqueous solution, twice with 20 ml of saturated sodiumbicarbonate aqueous solution, and once with 30 ml of saturated sodiumchloride aqueous solution sequentially; dried over anhydrous magnesiumsulfate; and concentrated. The residue was subjected to silica gelcolumn chromatography (eluent: methanol/ethyl acetate=5/95) to obtain 36mg of 3-phenoxy-2-pyridone.

¹H-NMR (395.75M Hz, CDCl₃) δ (ppm): 6.18 (t, J=6.9 Hz, 1H), 6.92 (dd,J=7.5, 1.7 Hz, 1H), 7.08 (brd, J=7.8 Hz, 2H), 7.15 (brt, J=7.5 Hz, 1H),7.19 (dd, J=6.7, 1.7 Hz, 1H), 7.36 (brt, J=7.5 Hz, 2H), 13.7 (brs, 1H)

PRODUCTION EXAMPLE 2

Under nitrogen atmosphere, 108 mg of the amide compound of the formula(F):

and 53 mg of 1,1,3,3-tetramethoxypropane were added into 2 ml of 85%phosphoric acid aqueous solution, and stirred at 50° C. for 9 hours. Thereaction mixture was left to cool to room temperature. In the reactionmixture were added 80 ml of ethyl acetate and saturated sodium chlorideaqueous solution, and separated. The organic layer was washed once with30 ml of saturated sodium chloride aqueous solution, twice with 20 ml ofsaturated sodium bicarbonate aqueous solution, and once with 30 ml ofsaturated sodium chloride aqueous solution sequentially; dried overanhydrous magnesium sulfate; and concentrated. The residue was subjectedto silica gel column chromatography (eluent: methanol/ethylacetate=5/95) to obtain 30 mg of the pyridone compound of the formula(G):

¹H-NMR (395.75M Hz, CDCl₃) δ (ppm): 3.52 (s, 3H), 6.21 (t, J=6.9 Hz,1H), 6.31 (s, 1H), 6.95 (s, 1H), 7.00 (dd, J=7.3, 1.5 Hz, 1H), 7.26 (dd,J=6.5, 1.7 Hz, 1H), 7.38 (d, J=9.1 Hz, 1H), 13.4 (brs, 1H)

PRODUCTION EXAMPLE 3

Under nitrogen atmosphere, 100 mg of the amide compound of the formula(F) and 49 mg of 1,1,3,3-tetramethoxypropane was added into 1.4 g ofpolyphosphoric acid, and stirred at 100° C. for 3 hours. The reactionmixture was left to cool to room temperature. In the reaction mixturewere added 150 ml of ethyl acetate and 10 ml of saturated sodiumchloride aqueous solution, and separated. The organic layer was washedonce with 50 ml of saturated sodium chloride aqueous solution, twicewith 50 ml of saturated sodium bicarbonate aqueous solution, and oncewith 35 ml of saturated sodium chloride aqueous solution sequentially;dried over anhydrous magnesium sulfate; and concentrated. The residuewas subjected to silica gel column chromatography (eluent:methanol/ethyl acetate=5/95) to obtain 38 mg of the pyridone compound ofthe formula (G).

PRODUCTION EXAMPLE 4

Under nitrogen atmosphere, 101 mg of the amide compound of the formula(F) and 38 mg of 1,1,3,3-tetramethoxypropane was added into 2 ml oftrifluoroacetic acid, and stirred at 70° C. for 9 hours. In this period,38 mg of 1,1,3,3-tetramethoxypropane was added every 1.5 hour (the totalamount of 1,1,3,3-tetramethoxypropane was 228 mg). The reaction mixturewas left to cool to room temperature. In the reaction mixture were added80 ml of ethyl acetate and 30 ml of saturated sodium chloride aqueoussolution, and separated. The organic layer was washed once with 30 ml ofsaturated sodium chloride aqueous solution, twice with 20 ml ofsaturated sodium bicarbonate aqueous solution, and once with 30 ml ofsaturated sodium chloride aqueous solution sequentially; dried overanhydrous magnesium sulfate; and concentrated. The residue was subjectedto silica gel column chromatography (eluent: methanol/ethylacetate=5/95) to obtain 44 mg of the pyridone compound of the formula(G).

PRODUCTION EXAMPLE 5

Under nitrogen atmosphere, 102 mg of the amide compound of the formula(F) and 50 mg of 1,1,3,3-tetramethoxypropane was added into 2 ml of12.5% hydrogen bromide in acetic acid, and stirred at 50° C. for 2 hoursand at 80° C. for 4 hours. The reaction mixture was cooled to roomtemperature. In the reaction mixture were added 80 ml of ethyl acetateand 30 ml of saturated sodium chloride aqueous solution, and separated.The organic layer was washed once with 30 ml of saturated sodiumchloride aqueous solution, twice with 20 ml of saturated sodiumbicarbonate aqueous solution, and once with 30 ml of saturated sodiumchloride aqueous solution sequentially; dried over anhydrous magnesiumsulfate; and concentrated. The residue was subjected to silica gelcolumn chromatography (eluent: methanol/ethyl acetate=5/95) to obtain 96mg of the pyridone compound of the formula (G).

PRODUCTION EXAMPLE 6

Under nitrogen atmosphere, 103 mg of the amide compound of the formula(F) and 50 mg of 1,1,3,3-tetramethoxypropane was added into 1 ml of 48%hydrobromic acid, and stirred at 80° C. for 4 hours. The reactionmixture was cooled to room temperature. In the reaction mixture wereadded 80 ml of ethyl acetate and 30 ml of saturated sodium chlorideaqueous solution, and separated. The organic layer was washed once with30 ml of saturated sodium chloride aqueous solution, twice with 20 ml ofsaturated sodium bicarbonate aqueous solution, and once with 30 ml ofsaturated sodium chloride aqueous solution sequentially; dried overanhydrous magnesium sulfate; and concentrated. The residue was subjectedto silica gel column chromatography (eluent: methanol/ethylacetate=5/95) to obtain 31 mg of the pyridone compound of the formula(G).

PRODUCTION EXAMPLE 7

Under nitrogen atmosphere, 104 mg of the amide compound of the formula(F) and 51 mg of 1,1,3,3-tetramethoxypropane was added into 2 ml of 1mol/l hydrogen chloride in acetic acid, and stirred at 80° C. for 1.5hours and at 100° C. for 6 hours. The reaction mixture was cooled toroom temperature. In the reaction mixture were added 80 ml of ethylacetate and 30 ml of saturated sodium chloride aqueous solution, andseparated. The organic layer was washed once with 30 ml of saturatedsodium chloride aqueous solution, twice with 20 ml of saturated sodiumbicarbonate aqueous solution, and once with 30 ml of saturated sodiumchloride aqueous solution sequentially; dried over anhydrous magnesiumsulfate; and concentrated. The residue was subjected to silica gelcolumn chromatography (eluent: methanol/ethyl acetate=5/95) to obtain 34mg of the pyridone compound of the formula (G).

PRODUCTION EXAMPLE 8

Under nitrogen atmosphere, 109 mg of the amide compound of the formula(F) and 53 mg of 1,1,3,3-tetramethoxypropane was added into 0.89 g oftrichloroacetic acid, and stirred at 100° C. for 6 hours. The reactionmixture was cooled to room temperature. In the reaction mixture wereadded 80 ml of ethyl acetate and 30 ml of saturated sodium chlorideaqueous solution, and separated. The organic layer was washed once with30 ml of saturated sodium chloride aqueous solution, twice with 20 ml ofsaturated sodium bicarbonate aqueous solution, and once with 30 ml ofsaturated sodium chloride aqueous solution sequentially; dried overanhydrous magnesium sulfate; and concentrated. The residue was subjectedto silica gel column chromatography (eluent: methanol/ethylacetate=5/95) to obtain 24 mg of the pyridone compound of the formula(G).

PRODUCTION EXAMPLE 9

Under nitrogen atmosphere, 119 mg of the amide compound of the formula(F) and 34 mg of 3-methoxypropenal was added into 2 ml of 12.5% hydrogenbromide solution in acetic acid, and stirred at 80° C. for 2 hours. Thereaction mixture was left to cool to room temperature. In the reactionmixture were added 80 ml of ethyl acetate and 30 ml of saturated sodiumchloride aqueous solution, and separated. The organic layer was washedonce with 30 ml of saturated sodium chloride aqueous solution, twicewith 20 ml of saturated sodium bicarbonate aqueous solution, and oncewith 30 ml of saturated sodium chloride aqueous solution sequentially;dried over anhydrous magnesium sulfate; and concentrated. The residuewas subjected to silica gel column chromatography (eluent:methanol/ethyl acetate=5/95) to obtain 100 mg of the pyridone compoundof the formula (G).

PRODUCTION EXAMPLE 10

Under nitrogen atmosphere, a mixture of 117 parts of the amide compoundof the formula (F), 57 parts of 1,1,3,3-tetramethoxypropane and 211parts of acetic acid was added into 628 parts of 30% hydrogen bromide inacetic acid which was previously cooled to 10 to 15° C., and stirred at50° C. for 8 hours. The reaction mixture was cooled to room temperature,and concentrated to the weight of 240 parts under reduced pressure. Themixture of the residue and 69 parts of methanol was added dropwise intothe mixture of 1160 parts of ice water and 316 parts of methanol at 0 to3° C. The pH of the mixture was adjusted to 7.3 with 40% sodiumhydroxide aqueous solution and saturated sodium bicarbonate aqueoussolution. The mixture was stirred for half a day being warmed to roomtemperature, and then filtered off. The filter cake was washed threetimes with 240 parts of water, and dried under reduced pressure. To thedry cake was added 343 parts of methanol, stirred for 1 hour heatingunder reflux condition, cooled to room temperature, and filtered off.The filter cake was washed with 114 parts of methanol, and dried underreduced pressure to obtain 96 parts of the pyridone compound of theformula (G) (content: 94%).

PRODUCTION EXAMPLE 11

Under nitrogen atmosphere, a mixture of 48 parts of the compound of theformula (F), 21 parts of 1,1,3,3-tetramethoxypropane, 36 parts ofsulfuric acid and 1037 parts of chlorobenzene was stirred at 80° C. for1 hour. The reaction mixture was cooled to room temperature. In thereaction mixture were added 2250 parts of ethyl acetate and 2500 partsof ice water, and separated. The organic layer was washed twice with1200 parts of water, once with 1200 parts of saturated sodiumbicarbonate aqueous solution, and once with 1200 parts of saturatedsodium chloride aqueous solution sequentially; dried over anhydroussodium sulfate; and concentrated. The residue was subjected to silicagel column chromatography (eluent: methanol/ethyl acetate=5/95) toobtain 32 parts of the pyridone compound of the formula (G).

PRODUCTION EXAMPLE 12

Under nitrogen atmosphere, a mixture of 96 parts of the amide compoundof the formula (F), 42 parts of 1,1,3,3-tetramethoxypropane, 49 parts ofsulfuric acid and 1618 parts of toluene was stirred at 60° C. for 3hour. The reaction mixture was cooled to room temperature. In thereaction mixture were added 2250 parts of ethyl acetate and 2500 partsof ice water, and separated. The organic layer was washed twice with1200 parts of water, once with 1200 parts of saturated sodiumbicarbonate aqueous solution, and once with 1200 parts of saturatedsodium chloride aqueous solution sequentially; dried over anhydroussodium sulfate; and concentrated. The residue was subjected to silicagel column chromatography (eluent: methanol/ethyl acetate=5/95) toobtain 65 parts of the pyridone compound of the formula (G).

PRODUCTION EXAMPLE 13

Under nitrogen atmosphere, a mixture of 48 parts of the amide compoundof the formula (F), 21 parts of 1,1,3,3-tetramethoxypropane, 33 parts ofmethanesulfonic acid and 1037 parts of chlorobenzene was stirred at 80°C. for 1 hour. The reaction mixture was cooled to room temperature. Inthe reaction mixture were added 2250 parts of ethyl acetate and 2500parts of ice water, and separated. The organic layer was washed twicewith 1200 parts of water, once with 1200 parts of saturated sodiumbicarbonate aqueous solution, and once with 1200 parts of saturatedsodium chloride aqueous solution sequentially; dried over anhydroussodium sulfate; and concentrated. The residue was subjected to silicagel column chromatography (eluent: methanol/ethyl acetate=5/95) toobtain 34 parts of the pyridone compound of the formula (G).

PRODUCTION EXAMPLE 14

Under nitrogen atmosphere, a mixture of 112 parts of the amide compoundof the formula (F), 49 parts of 1,1,3,3-tetramethoxypropane, 78 parts ofmethanesulfonic acid and 1894 parts of toluene was stirred at 80° C. for2 hour. The reaction mixture was cooled to room temperature. In thereaction mixture were added 2250 parts of ethyl acetate and 2500 partsof ice water, and separated. The organic layer was washed twice with1200 parts of water, once with 1200 parts of saturated sodiumbicarbonate aqueous solution, and once with 1200 parts of saturatedsodium chloride aqueous solution sequentially; dried over anhydroussodium sulfate; and concentrated. The residue was subjected to silicagel column chromatography (eluent: methanol/ethyl acetate=5/95) toobtain 85 parts of the pyridone compound of the formula (G).

PRODUCTION EXAMPLE 15

Under nitrogen atmosphere, a mixture of 96 parts of the amide compoundof the formula (F), 42 parts of 1,1,3,3-tetramethoxypropane, 55 parts ofchlorosulfonic acid and 746 parts of chloroform was stirred at 60° C.for 2.5 hours. The reaction mixture was cooled to room temperature. Inthe reaction mixture were added 2255 parts of ethyl acetate, 500 partsof ice water and 1200 parts of saturated sodium bicarbonate aqueoussolution, and separated. The organic layer was washed twice with 1200parts of water, once with 1200 parts of saturated sodium bicarbonateaqueous solution, and once with 1200 parts of saturated sodium chlorideaqueous solution sequentially; dried over anhydrous sodium sulfate; andconcentrated. The residue was subjected to silica gel columnchromatography (eluent: methanol/ethyl acetate=5/95) to obtain 73 partsof the pyridone compound of the formula (G).

PRODUCTION EXAMPLE 16

Under nitrogen atmosphere, a mixture of 96 parts of the amide compoundof the formula (F), 42 parts of 1,1,3,3-tetramethoxypropane, 81 parts ofchlorosulfonic acid and 2070 parts of chlorobenzene was stirred at 80°C. for 2 hour. The reaction mixture was cooled to room temperature. Inthe reaction mixture were added 2250 parts of ethyl acetate and 2500parts of ice water, and separated. The organic layer was washed twicewith 1200 parts of water, once with 1200 parts of saturated sodiumbicarbonate aqueous solution, and once with 1200 parts of saturatedsodium chloride aqueous solution sequentially; dried over anhydroussodium sulfate; and concentrated. The residue was subjected to silicagel column chromatography (eluent: methanol/ethyl acetate=5/95) toobtain 73 parts of the pyridone compound of the formula (G).

PRODUCTION EXAMPLE 17

Under nitrogen atmosphere, a mixture of 48 parts of the amide compoundof the formula (F), 21 parts of 1,1,3,3-tetramethoxypropane, 41 parts ofp-toluenesulfonic acid mono-hydrate and 1037 parts of chlorobenzene wasstirred at 80° C. for 2 hour. The reaction mixture was cooled to roomtemperature. In the reaction mixture were added 2250 parts of ethylacetate and 2500 parts of ice water, and separated. The organic layerwas washed twice with 1200 parts of water, once with 1200 parts ofsaturated sodium bicarbonate aqueous solution, and once with 1200 partsof saturated sodium chloride aqueous solution sequentially; dried overanhydrous sodium sulfate; and concentrated. The residue was subjected tosilica gel column chromatography (eluent: methanol/ethyl acetate=5/95)to obtain 32 parts of the pyridone compound of the formula (G).

Next, the process for producing the starting compound used in the aboveProduction Example will be illustrated as Reference Production Example.

REFERENCE PRODUCTION EXAMPLE 1

Under nitrogen atmosphere, 1.57 g of 2-chloro-3-oxobutylamide, 1.08 g ofphenol and 1.7 ml of triethylamine were added into 20 ml ofN,N-dimethylformamide, and stirred at 80° C. for 6 hours and at 100° C.for 4 hours. The reaction mixture was left to cool to room temperature.In the reaction mixture were added 100 ml of ethyl acetate and 30 ml ofsaturated sodium chloride aqueous solution, and separated. The organiclayer was washed once with 20 ml of saturated sodium chloride aqueoussolution, twice with 20 ml of hydrochloric acid (1 mol/l), and once with20 ml of saturated sodium chloride aqueous solution sequentially; driedover anhydrous magnesium sulfate; and concentrated. The residue wassubjected to silica gel column chromatography (eluent: hexane/ethylacetate=6/4) to obtain 0.44 g of 3-oxo-2-phenoxybutylamide.

3-Oxo-2-phenoxybutylamide

REFERENCE PRODUCTION EXAMPLE 2

Under nitrogen atmosphere, 8.92 g of 2-chloro-3-oxobutanamide, 20.3 g ofthe compound of the formula (H):

and 16.7 ml of triethylamine were added into 120 ml ofN,N-dimethylformamide, and stirred at 70° C. for 1 hour and 100° C. for4.5 hours. The reaction mixture was left to cool to room temperature. Inthe reaction mixture were added 200 ml of ethyl acetate and 30 ml ofsaturated sodium chloride aqueous solution, and the mixture wasseparated. The organic layer was washed once with 30 ml of saturatedsodium chloride aqueous solution, twice with 30 ml of hydrochloric acid(1 mol/l), and once with 30 ml of saturated sodium chloride aqueoussolution sequentially; dried over anhydrous magnesium sulfate; andconcentrated. The residue was subjected to silica gel columnchromatography (eluent: hexane/ethyl acetate=6/4) to obtain 17.9 g ofthe compound of the formula (F).The Compound of the Formula (F)

m.p.: 192.3° C.

Next, the process for producing the herbicidal compound by using thecompound of the formula (G) obtained the above Production Example as astarting compound will be illustrated as Reference Production Example.

REFERENCE PRODUCTION EXAMPLE 3

Into 15 ml of dichloroethane were added 0.5 g of the compound of theformula (G) and 8 mg of rhodium (II) trifluoroacetate dimmer, and 0.15 gof methyl diazoacetate was added dropwise at 80° C. over 3 hours. Afterthe addition, the mixture was stirred at 80° C. for 1 hour, andconcentrated. The residue was subjected to silica gel columnchromatography (eluent: hexane/ethyl acetate=3/1 to 0/1) to obtain 0.18g of the unreacted starting compound of the formula (G) and 0.34 g of3-(2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine)-2-(methoxycarbonylmethoxy)pyridine:

¹H-NMR (300M Hz, CDCl₃, TMS δ (ppm)): 3.50 (3H, q, J=1.0 Hz), 3.70 (3H,s), 4.90 (1H, d, J=15.8 Hz), 4.97 (1H, d, J=15.8 Hz), 6.29 (1H, s),6.90–6.95 (2H, m), 7.32 (1H, dd, J=1.9 Hz, 7.7 Hz), 7.37 (1H, d, J=8.7Hz), 7.92 (1H, dd, J=1.9 Hz, 4.9 Hz)

INDUSTRIAL APPLICABILITY

The present pyridone compound can be produced from the present amidecompound by the present process.

1. The process for producing a pyridone compound of the formula (2):

wherein R is defined below; which comprises making an amide compound ofthe formula (1):

wherein R represents an optionally substituted phenyl; react with atleast one compound selected from the group consisting of3-alkoxypropenal of the formula (3), 3,3-dialkoxypropanal of the formula(4), 1,3,3-trialkoxy-1-propene of the formula (5),1,1,3,3-tetraalkoxypropane of the formula (6), and malonaldehyde:

wherein R⁹ represents alkyl (e.g. C1–C3 alkyl such as methoxy, ethoxyand the like); in the presence of a protonic acid.
 2. The processaccording to claim 1, wherein the at least one compound is the3-alkoxypropenal of the formula (3) or the 1,1,3,3-tetraalkoxypropane ofthe formula (6).
 3. The process according to claim 1, wherein the atleast one compound is the 3-methoxypropenal or1,1,3,3-tetramethoxypropane.
 4. The process according to claim 1,wherein the protonic acid is hydrogen halide, phosphoric acid,polyphosphoric acid, sulfuric acid, trihaloacetic acid, or sulfonicacid.
 5. The process according to claim 1, wherein the R, in the amidecompound of the formula (1) and the pyridone compound of the formula(2), is the radical of the following formula:

wherein R¹ represents a halogen atom or nitro, and R² represents ahydrogen or halogen atom.